The p75(NTR)-induced apoptotic program develops through a ceramide-caspase pathway negatively regulated by nitric...

Area of Science:

• Cell Biology
• Neuroscience
• Biochemistry

Background:

• Neurotrophin receptor p75(NTR) plays a role in neuronal development and survival.
• Neurotrophic factors like NGF influence neuronal fate through various receptors.
• Apoptosis, or programmed cell death, is crucial for development and tissue homeostasis.

Purpose of the Study:

• To investigate the molecular mechanisms by which p75(NTR) influences apoptosis in neuroblastoma cells.
• To elucidate the roles of ceramide, caspases, and nitric oxide (NO) in p75(NTR)-mediated cell death.
• To explore the protective effects of NGF and NO against p75(NTR)-induced apoptosis.

Main Methods:

• Utilized SK-N-BE neuroblastoma cell clones transfected with p75(NTR) and lacking Trk receptors.
• Measured levels of ceramide and activity of caspases.
• Assessed the impact of nerve growth factor (NGF) treatment, exogenous ceramide, and nitric oxide (NO) modulation on apoptosis.
• Compared apoptotic and resistant cell clones regarding nitric-oxide synthase activity.

Main Results:

• p75(NTR)-expressing cells showed increased ceramide and caspase activity, correlating with spontaneous apoptosis.
• NGF treatment and caspase blockers reduced apoptosis in p75(NTR)-expressing cells.
• Exogenous ceramide enhanced caspase activity and apoptosis in both wild-type and p75(NTR)-expressing cells.
• Nitric oxide (NO) synthase activity was inversely correlated with apoptosis, and NO donors protected against cell death.

Conclusions:

• The p75(NTR) receptor, in the absence of NGF, initiates an apoptotic cascade involving ceramide generation and caspase activation.
• NGF and NO act as protective agents, intervening in the ceramide-caspase pathway to prevent apoptosis.
• These findings highlight a novel signaling pathway regulated by p75(NTR) in neuroblastoma cell death.